The present invention relates to crystals of p1-(2xe2x80x2-deoxycytidine 5xe2x80x2-)P4-(uridine 5xe2x80x2-)tetraphosphate (dCP4U) or a pharmaceutically acceptable salt thereof (hereinafter may be referred to simply as xe2x80x9cdCP4Uxe2x80x9d) which is useful as a therapeutic agent for chronic bronchitis, sinusitis, and the like; a process for producing the crystals; and a process for efficiently producing dCP4U.
dCP4U represented by the following formula (I): 
or a salt thereof is a selective agonist to P2Y2 purine receptor and/or P2Y4 purine receptor and is a compound which is expected to be developed as a therapeutic agent for chronic bronchitis, sinusitis, and the like (See WO 98/34942).
Until now, it has not been possible to obtain dCP4U in crystal form, and dCP4U has been prepared only in the form of white powder (white solid) through freeze-drying. The conventionally obtained powdery products of dCP4U have a purity as low as 82% (measured by HPLC). Particularly, it is difficult to separate uridine 5xe2x80x2-triphosphate (UTP) serving as a starting material from dCP4U, and highly purified dCP4U has been produced only with great difficulty through a conventionally employed ion-exchange chromatography (WO 98/34942).
The above white powder of low purity has disadvantages such as hygroscopicity. Therefore, preparation of a pharmaceutical from dCP4U must be carried out in a special apparatus in which moisture is closely controlled. Even after preparation of a pharmaceutical, the product must be tightly packaged. In addition, since the pharmaceutical has a very short available period due to poor stability of the powder product, obtaining highly purified and stable crystals of dCP4U has been desired. dCP4U is synthesized from 2xe2x80x2-deoxycytidine 5xe2x80x2-monophosphate (dCMP) and UTP by use of an activating agent such as dicyclohexylcarbodiimide (DCC). However, conventional processes provide a considerably low synthetic yield; i.e., as low as approximately 9 wt. % (see Example 20 of WO 98/34942), and can never serve as a practical process. Accordingly, development of a process for producing dCP4U at high yield and on a large scale has also been desired.
In view of the foregoing, an object of the present invention is to provide stable crystals of dCP4U which is suitable for preparing drugs. Another object of the invention is to provide a process for producing the crystals. Still another object of the invention is to provide an efficient process suitable for large scale production of dCP4U.
The present inventors have conducted intensive studies on stabilization of dCP4U, and have found that dCP4U having a purity of 95% or more can be prepared through anion exchange chromatography in combination with chromatography employing activated charcoal (activated-charcoal chromatography) and that dCP4U crystals can be produced from such highly-purified dCP4U. The thus-obtained dCP4U crystals have proven to possess a purity considerably higher than that of conventionally produced dCP4U powder, no hygroscopicity and high stability.
The inventors have also conducted intensive studies on methods for synthesizing dCP4U by use of inexpensive uridine 5xe2x80x2-monophosphate (UMP) instead of expensive UTP, and have found that dCP4U can be effectively produced by use of diphenyl phosphorochloridate (DPC) and a pyrophosphate (PPi). The present invention has been accomplished on the basis of these findings.
Accordingly, the present invention provides crystals of dCP4U.
The present invention also provides a process for producing crystals of dCP4U, which process comprises purifying crude dCP4U through anion exchange chromatography and activated-charcoal chromatography and adding a hydrophilic organic solvent to a solution of purified dCP4U, to thereby precipitate dCP4U in the form of crystals.
The present invention also provides a process for producing dCP4U which comprises reacting UMP, dCMP, DPC, and PPi.